Spasmolytic pipergzjnes



come & Co. (U. S. A.) Inc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application December 28, 1954, Serial No. 478,211

Claims. (Cl. 260-468) The present invention relates to a group of quaternary ammonium salts derived from N-acyl-N-alkyl piperazines and a method of preparing them. These compounds can be represented by the formula n-o 0--N' N wherein R is selected from the class consisting of the 1- phenylcyclohexyl and 9-xanthenyl radicals, R and R" are lower alkyl radicals having between them at least three and not more than four carbon atoms and X" is the anion of a nontoxic acid.

The compounds of the above class have atropine-like activities as spasmolytics and the potency of the members varies from about a third that of atropine to somewhat more than equipotency. It will be realized that since the therapeutic utility of such compounds depends not only on inherent activity but also upon ease of absorption, resistance to degradation and absence of side effects, it does not always follow that the most active member of a series is the most useful.

These compounds are advantageously prepared by the following reaction sequence RI! wherein R, R and R" and X- have the above-mentioned values. The anion X is 'of little consequence in such active compounds since the physiological activity resides in the cation. As prepared, X- may be chloride, bromide, iodide, methanesulfonate, ethanesulfonate, toluenesulfonate or the like. By exchange reactions of the conventional sort one of .the original variants of X might be replaced by malate, succinate, fumarate, tartrate or oleatc. The salts obtained through these variations of X may in some cases have special advantages due to solubility, ease of crystallization, lack of objectionable taste, etc., but these are all subsidiary to the main physiological action which is independent of the character of X. Hence, all variants of X" are considered equivalents.

EXAMPLE I The N-methylpiperazine amide of I-phenylcyclohexane carboxylic acid l-phenylcyclohexane carboxylic acid was converted to the acid chloride (B. P., 127 at 2-3 mm.) by treatment with thionyl chloride. In a little dry benzene 7.4 g. (0.033 mole) of this acid chloride was mixed with 6.6 g. (0.066 mole) of methylpiperazine. The reaction mixture was held under gentle reflux for hours, then cooled and partitioned between water and ether. The ethereal United st o 4, 2,742,412 Patented Apr. .11, .1956

1 layer was then extracted with dilute hydrochloric acid from :which 9.2 g. of water-insoluble base precipitated addition-of alkali. The base Was a solid melting at 96.- 98"... Whendissolved in absolute e-thanol and neutralized with hydrogen chloride it forms a hydrochloride melting at 268.

When dissolved in acetone the amide base reacted with ethyl iodide to form a solid ethiodide. This ethiodide. after recrystallization from ethanol-ether mixture, melted at 206.

The ethiodide was converted by the action of silver chloride .to the etho-chloride.

The base reacted with ethyl ethane sultonate to form the N '-ethyl ethane sulfonate salt.

When dissolved'in acetone the amide base (2.6 g.) reacted with isopropyl iodide (2 g.) to yield the N'- isopropiodide which was recrystallized from absolute ethanol and then melted at 172.

EXAMPLE H The N-methylpiperazine amide of xanthene-9-carboxylic acid used directly.

The acid chloride from 8.4 g. of acid was added to 7 g. of methylpiperazine in 20 cc. of benzene. The reaction mixture was warmed on the steam bath for hour and then cooled and partitioned between water and ether. The ethereal layer was then extracted with dilute hydrochloric acid to remove the amide base which precipitated as a low-melting solid "on basification. This base forms a hydrochloride melting at 266.

When dissolved in acetone the amide base reacted with excess ethyl iodide to give an ethiodide that melted at 244 with decomposition. methanol. Similarly an etho-bromide was formed by reaction with ethylbromide. With isopropyl iodide the isopropiodide was formed, M. P. 25 6 dec.

EXAMPLE III The N'-ethylpiperazine amide of xanthene-9-carboxylic acid When xanthene-9-carboxylic chloride (Example II) was reacted with ethyl piperazine by the methods of Examples I and H, the N'-ethylpiperazine amide was formed. This substance is an oil. Dissolved in acetone it reacted with ethyl p-toluenesulfona-te to give the quaternary p-toluene sulfona-te. With ethyl iodide it afforded the ethiodide, M. P. 245-246".

We claim:

1. A quaternary ammonium salt represented by the formula R RCON ri It was recrystallized from I 3 te 9' 5. A method of preparing compounds of the formula the mid of a nontoxic acid, which comprises reacting a compoundof the fo mula RCON' H N X- RCON/ H U with a quaternizing reagent of the formula R" X wherein R, R, R" and X have the above indicated values and recovering the product.

wherein R is a radical selected from the class consistingof the 9-xanthenyl and l-phenylcyclohexyl radicals, R and R are lower alkyl radicals having together at least threetand not more than four carbon atoms and X is v a Noreferences cited. 

1. A QUATERNARY AMMONIUM SALT REPRESENTED BY THE FORMULA
 5. A METHOD OF PREPARING COMPOUNDS OF THE FORMULA 